My Work
Our focus is on Parkinson's disease. We have identified a novel agent that can protect neurons involved in the disease from being destroyed by the pesticide rotenone. The agent, called L-AP4, activates a critical group of receptors called group III metabotropic glutamate receptors and may be a promising drug target.
We have also found that the disease may be caused by an environmental-genetic impact on neurons that produce dopamine, the neurotransmitter that controls body movement. The presence of mutated parkin genes, combined with the toxic effects of the chemical rotenone, results in a cascade of highly toxic free radicals, the destruction of microtubules that transport dopamine to the brain’s movement center, and eventual death of the dopamine-producing neurons.
This study shows how an environmental toxin and a gene linked to Parkinson's disease affect the survival of dopamine neurons by dueling on a common molecular target—microtubules—that are critical for the survival of dopamine-producing neurons.
Based on these findings, we have identified several ways to stabilize microtubules against the onslaught of rotenone. These results ultimately may lead to novel therapies for Parkinson's disease.
My Research
My research program is focused on parkin, one of the most prevalent genetic factors in Parkinson’s disease. Our goal is to find out how mutations of parkin, a protein-ubiquitin E3 ligase widely expressed in many tissues, lead to specific degeneration of dopaminergic neurons in substantia nigra and ensuing Parkinson’s disease.
To achieve this, we adopted two approaches. First, we want to delete the parkin gene in mice to see whether we can generate a mouse model for Parkinson’s disease, mimicking the recessive mutations of parkin in human patients. Second, we want to study the biological functions of parkin by identifying the proteins with which it interacts, its subcellular localization, and whether it is doing something special in dopaminergic neurons.
We have found that parkin binds to a/b tubulin heterodimers and microtubules very strongly and increases the ubiquitination and degradation of α- and β-tubulins.
In addition, we also found that parkin was recruited to the centrosome in a microtubule-dependent manner when protein degradation through the 26S proteasome was inhibited.
These novel findings on the interaction between parkin and tubulins suggest that microtubules play a critical role in Parkinson’s disease. Further studies are underway to establish such a link.